After eight years of ethical and political disagreement,
a change in the White House may touch off an explosion of
stem cell research at Johns Hopkins and elsewhere. But
already, new and less-controversial advances in stem cell
creation are making the search for cures even more
promising.

By Michael Anft

As
election returns rolled in on the night of November 4,
researchers at labs on the Johns Hopkins medical campus
raised glasses and celebrated the victory of Barack Obama.
These weren't the street revelers who overtook downtowns
across the country — no one would peg this reserved
bunch as Obama's base. In fact, many were noncitizens who
couldn't even vote. Some of the celebrants might have
applauded his economic plans, his directional shift on
Iraq, or something not having to do with their work. But
most were single-issue enthusiasts. Obama's promise that,
under his administration, the rigors of science would be
undertaken without interference — to "restore science
to its rightful place, and wield technology's wonders to
raise health care's quality," as he put it a couple of
months later at his inauguration — is what lit up the
white-coat crowd. That, and the minuscule speck of biology
lurking in the nucleus of Obama's lofty language: the stem
cell.

In the months following that night, researchers who study
the stem cell have remained buoyant. "It almost feels like
a liberation for people who do science," says Chi V. Dang,
Med '82, a witness to the jubilation as well as the vice
dean of research at the School of Medicine. He also serves
as director of the Johns Hopkins Institute for Cell
Engineering, where scientists grow stem cells every day to
seek new answers to old biological questions. Dang conducts
research on cancer in his own lab using stem cells —
the building blocks of life that construct blood vessels,
the nervous system, organs, and everything else that makes
us human.

Since first being grown in a lab in 1998, human stem cells
have been touted as the key to understanding the mechanisms
that underlie long-incurable diseases, an answer to cancer,
a way to get paralyzed limbs moving, and a step toward
using cells as medicine. One day, scientists envision,
therapies wrought from various types of stem cells will be
used to treat entire classes of diseases and injuries
— perhaps turning chemical-based drugs and the side
effects that come with them into relics. Scientists have
coined a name for the field that taps stem cells' promise
in rebuilding human tissue: regenerative medicine.

Stem cells have been regarded as the best — perhaps
the last — hope for patients with certain diseases
such as diabetes; if stem cells could be used inside the
body to grow the pancreatic islet cells that produce
insulin — cells that are ravaged by an immune
response in diabetics — then, one day, injecting them
into patients might reverse the disorder. The same might be
true for Parkinson's disease, which afflicts 2 percent of
people over age 65, and thousands of younger people. If
stem cell therapies could be developed that would repair or
replace damaged or dead dopamine neurons in the brain,
sufferers would no longer lose control of their movements.
Stem cell research affords scientists the chance to see if
they can develop personalized "drugs" that would work
throughout the body, or to uncover the secrets behind the
development of human tissues and the origins of disease. No
other therapy or group of therapies comes close to its
potential impact.

Like other scientific powerhouses unobservable to the naked
eye — think of the atom or the bacterium — the
stem cell has become magnified not only by the microscope
but by public debate. In 2001, then president George W.
Bush, siding with social and religious conservatives who
believe life begins at conception, ordered restrictions on
federal funding of stem cell research derived from human
embryos. In the process of extracting stem cells,
scientists destroy days-old embryos that have been
fertilized in test tubes, originally to artificially
impregnate women. Typically, those embryos left over from
in vitro fertilization are frozen or thrown out as medical
waste.

In the intervening years, dozens of scientists moved abroad
to do embryonic stem cell research in countries such as
Great Britain, Singapore, and Sweden, where laws and
funding favored them. Some stayed behind to work with more
than 60 government-approved embryonic stem cell lines
created before Bush's order took effect, even though most
of those lines proved to be tainted by mouse viruses, or
developed genetic changes that occur over time. Other
bioscientists decided to do research that had nothing to do
with stem cells. They avoided hassles with paperwork and
keeping their federally supported labs separate from labs
where researchers performed nonsanctioned stem cell
experiments fueled by a smattering of private grants and
outlays from several states, including California (which
pledged to invest $3 billion) and Maryland.

Because of the strictures, many bench workers and
professors believe that the pace of embryonic stem cell
work has moved too slowly.

How handcuffed have researchers been? The National
Institutes of Health — the biggest repository of
federal research dollars, with an annual grant budget of
nearly $30 billion — approved only about $2 billion
for all types of stem cell research last year. That's less
than 7 percent of NIH's total expenditures, for the area of
research that scientists are calling "the gateway to
21st-century medicine." Obama vowed to overturn
restrictions and free up more federal dollars for stem cell
research. His opponent, John McCain, vacillated on the
issue. Hence, the euphoria among bioresearchers that night
in November. In March, Obama validated their exuberance,
allowing researchers to apply for federal grant dollars to
work with embryonic stem cell lines created with the help
of private or state money.

"When you're told you can do ethical research in an
unfettered way, you have the opportunity to play out any
scenario, to fulfill the potential that comes from the art
of doing research," says Dang.

But the liberation Dang feels isn't limited to new
opportunities to plumb the depths of stem cells taken from
destroyed embryos. Two years ago, stem cell scientists
envisioned an arc connecting only embryonic stem cells to
cures. But, as often happens in science, the line from the
past to the future is jagged and frequently interrupted,
and can take a sharp turn or two. Researchers in Japan and
the United States have devised a way to unleash the power
of the stem cell without destroying embryos — the
concern that led Bush to limit stem cell research in the
first place. Theologians and bioethicists who are squeamish
about embryos have no problem with this newer type of stem
cell. Researchers are intrigued by it as well. The
converted adult cells, they say, offer advantages over
cells taken from embryos because they could be altered,
then injected into their donor. By using a person's own
stem cells as medicine, doctors could eliminate worries
about a patient's immune system rejecting the cells, as
they might if they were derived from embryos.

If nothing else, so-called induced stem cells call into
question what the future of research might be. They give
scientists a lot to ponder: Will they still need embryonic
stem cells for certain types of experiments that lead to
treatments, or to learn the biomechanics of disease? Or
will they be able to skirt ethical misgivings by
exclusively using cells that come from a patient's own
body?

Taking cells from a patient is simple enough. A surgeon
simply removes a plug of skin with a scalpel and caps it in
a test tube. But to reprogram those cells requires
scientists at the bench to do nothing less than turn back
time, if only to get a glimpse of the future.

Cassandra
Obie has grown cultures for Johns Hopkins
researchers for decades. But last May, while manning her
well-lit workspace at the
Johns Hopkins Institute for
Genetic Medicine, she began receiving a different kind
of
request. Physicians treating people with amyotrophic
lateral sclerosis (ALS, more commonly known as Lou Gehrig's
disease), Huntington's disease, Parkinson's, and
schizophrenia sent her biopsies — "a three-millimeter
standard punch of skin" for each patient, she says —
and asked her to grow primary tissue cells called
fibroblasts from them. The cells would be used for research
in mouse models; the patients agreed to undergo the
biopsies in hopes that the work would provide clues, and
perhaps cures, to their diseases.

Obie, a senior research specialist, takes a small piece of
the biopsied tissue apart with a scalpel, then digs the
scalpel into a culture dish, forcing the skin cells to
adhere to the cuts she makes. The process of taking a cell
back to its infancy — of turning back the clock
— is rooted in the technical, not the miraculous.
"You have to embed it. If you see the piece of skin
floating around," she says, "you won't grow fibroblasts."

Within three days to a week, she'll see fibroblasts, thin
fibers that stretch out in all directions like microscopic
tree branches from pieces of biopsied skin. Once a week,
she gives them a bath of fresh medium — made up of
the fetal serum of a cow, as well as a combination of
antibiotics and non-essential amino acids — before
returning them to an incubator. After cells have grown to
cover more than half the dish, she scoops them out and
places them into tissue culture flasks. When the flasks
become full, she sends the five- to six-week-old cells
upstairs to another lab in the Broadway Research Building,
where Institute for
Cell Engineering investigators wait for
them to be made young again.

That's Jason Chiang's job. A graduate student in
neuroscience in the lab of associate professor Hongjun
Song
(and a physician in his native Taiwan), Chiang transforms
fibroblasts into induced pluripotent stem cells (iPS cells)
— a mouthful that means adult tissue cells that have
been reprogrammed into cells that, like embryonic stem
cells, can make a variety of cell types. Chiang watches as
the fibroblasts develop dots — concentrated bits of
energy that will help them grow — under the
microscope.

It takes a month for fibroblasts to morph into iPS cells,
which very closely resemble embryonic stem cells, or ESCs.
Chiang varies the medium they grow in daily, moving them to
new dishes as they multiply. By changing the medium over
the next three to four weeks, he guides them to
"differentiate" into neural stem cells — the ones
Chiang and Song need to investigate the workings of the
brain and diseases that affect it. Otherwise, they could
become stem cells that form any other part of the body.
Chiang makes sure to use only the first batches of cells
from a dish, ones that haven't lived long enough to develop
traits that could lead to bad science. "We try to avoid
genetic mutations" that could wreck results, Chiang
says.

In all, Chiang has made about 1 million neural stem cells
in the last year or more so that he can inject a small
amount of them into the embryos of mice. After the mice are
born, the researchers will observe them for signs that the
stem cells have been integrated into the brain. If they
have, Song says, "it can give us a preclinical model for
human diseases."

Song says that iPS cells offer researchers several
advantages over ESCs. Since the stem cells are derived from
a patient's own cells, it is less likely the patient's
immune system will reject them. They also are much less
likely to form tumors than ESCs. After creating pancreatic
islet cells during the iPS-making process, Song explains,
"we could replace a [diabetes] patient's bad cells with
ones that could make insulin. They would become part of the
patient's pancreatic tissue. So, you would only need to
inject them once" — which would limit possible
complications and help people who have been financially
battered by having to pay thousands of dollars each year
renewing their prescriptions.

The newer type of stem cells also makes patient-specific
genetic manipulations possible, meaning that some diseases
might one day be reversed, says Ted Dawson, co-director of
the Institute for
Cell Engineering. "We may be able to use
these cells to deal with a translocated chromosome in an
individual with leukemia," he says. "Eventually, we might
be able to take a skin biopsy from a patient, correct the
abnormality in the lab, give the patient chemotherapy to
kill off the blood marrow cells, and then inject the
patient with the corrected cells."

Because iPS cells are derived from a patient, they could be
used in a dish to test drugs to see if they will stamp out
a disease. "If you can get the dopamine neurons of a
patient with Parkinson's, you can see what works on them
and what doesn't," says Song.

For science to garner as many answers as possible, it needs
all the tools it can wrap its gloved hands around, say
researchers.

Song and his wife, Guoli Ming, also an associate professor
in neurology,
investigate how to activate adult stem cells
that weren't made in a lab but naturally live on in the
bodies of people — even the elderly — long
after the brain and nervous system have been formed.
Researchers hope that tweaking this third type of stem cell
can help them cure disease.

Adult stem cells can regenerate themselves even after they
are done forming nerves and organs — a power that
distinguishes them from embryonic stem cells and iPS cells.
Unlike the other two types, adult cells have been used for
years in bone marrow transplants to treat people with blood
disorders. Experimentally, researchers at the Johns
Hopkins-affiliated Kennedy Krieger Institute are searching
for ways to activate adult stem cells in the spinal cord to
help some of the 250,000 paralyzed people nationally regain
some mobility.

By experimenting with all types of stem cells, Song says
his lab has begun to learn how plastic existing stem cells
in the brain are and how anti-depression drugs activate
them. The lab's goal now is to learn how to use cells'
flexibility to develop treatments for conditions such as
autism and schizophrenia.

"That shows you how broad an impact one stem cell inquiry
can have," he says. "Can you imagine the impact we can have
when science has thousands going at the same time?"

The 2007
announcement of Japanese researcher Shinya
Yamanaka's discovery that regular human adult cells could
be returned to their stem cell state — and the
success in replicating his experiment since then —
would seem, in one light, to make the controversial
embryonic stem cell passť. But it's not that simple. For
science to garner as many answers as possible to the
riddles of disease, it needs all the tools it can wrap its
gloved hands around, say Johns Hopkins researchers who use
stem cells to unravel them. That includes cells made from
embryos.

"If there's such a thing as a gold standard in this type of
research, the embryonic stem cell is it," says Jeffrey
Rothstein, a professor of neurology at the
School of
Medicine and a longtime researcher of ALS. An adult cell
has been affected by its environment and gone through
changes as it has become damaged or developed resistance to
damage. It has been exposed to viruses. Will all that
affect stem cells derived from it? Given that stem cells
may one day be used to grow replacement organs and to cure
ailments of the circulatory and nervous systems, any
unintended consequences are likely to be harmful. For now,
it is best for scientists to play out their differences in
the labs, so humans aren't endangered by whatever may lurk
deep inside the cell. At this point, iPS cells are
intriguing but essentially limited.

"It's a bit like a brand new tire versus a retread,"
Rothstein explains. "They look the same, but one is new and
the other is made of old, used stuff that may not last as
long. Maybe the glue will come loose one day and the tread
will fall off. We just don't know." What's important, say
Rothstein and others, is that scientists have enough
funding to do a wide variety of research, including
comparing the two types of stem cells and seeing what the
differences are.

Some scientists worry that iPS cells made from older tissue
may exhibit signs of advanced aging. Dolly, the lamb cloned
in Scotland from the cells of a six-year-old sheep, lived
only half a typical ovine lifespan. Was it because she was
cloned using the cells of an older sheep? The issue of iPS
cells' "pluripotence" — the ability to become any
type of cell in the body — is debatable as well.
While embryonic cells unquestionably demonstrate
pluripotence, it isn't fully known whether reprogrammed
adult cells are equally versatile, or whether their genetic
material is faithfully replicated. What's more, iPS cells
don't "live" nearly as long as those made from embryos. And
doing what Obie and Chiang do takes a lot of money. "The
technology is still new," says Song. "It is very expensive
to reprogram cells."

Because iPS cells are reprogrammed using genes associated
with cancer, researchers worry that therapies might pose a
danger to patients in the longer term — something
that would limit their clinical applications until
scientists can figure out how to use different genes.
Already, possibly with the aid of political change, ESCs
are ahead on the clinical front. Days after Obama's
inauguration, the Food and Drug Administration announced
its approval of the first clinical human trials using
embryonic stem cells. The California firm that won approval
had been asking the agency since 2005 for permission to run
trials on people with spinal cord injuries. During the
trials, they will be injected with stem cells capable of
reversing paralysis in experimental rodents.

Physicians who deal with particularly difficult diseases,
like ALS, say that keeping all types of stem cells on the
lab bench makes the most sense. Some type of stem cell
therapy may be the last hope for sufferers of a disease
that strips bodies of their ability to feel or move but
leaves minds intact to assess the damage. The FDA hasn't
approved an ALS drug since 1995. Unlike Parkinson's
disease, which centers upon one cell — the dopamine
neuron — ALS attacks a complex system of cells,
making it incredibly difficult to understand. While Ted
Dawson and others can envision the development of
treatments for Parkinson's, ALS researchers worry about how
to identify how ALS comes into being, how to stop its
progression, how to repair existing damage, and how to
eliminate it from a patient's system. The use of iPS cells
as the lone research tool likely won't do much to speed up
the pace.

"We still need to work through some of the technical
issues," says Rothstein. "It would take three years with
the technology we have now to connect one nerve in the
spinal cord to one in the foot. One of the problems [with
iPS cells] is that they grow so slowly."

Other roadblocks exist, and they point up how far
researchers have to go. If physicians had stem cell
therapies at their disposal, they might be able to inject
people with cells that could help them rebuild nerves and
tissue, but they'd still lack the targeting methods
necessary to make sure they do the right job in the right
place — another aspect of stem cell research that
needs to be figured out. "It's like having your computer
screen go black," says Rothstein. "You could go to Radio
Shack and buy these little processors, and then open up the
back of your computer and toss them in there. But would
they work?"

To come up with better models for ALS and some genetic
neurological disorders, Douglas Kerr, an associate
professor of
neurology, says that ongoing research with
human ESCs is indispensable. Stem cells from ESCs feature
all the guides for the growth of new axons and neurons, he
says: "It's only been in the last five years that we've
figured out how to generate the right kinds of stem cells.
We're really in time zero. We've learned how to generate
millions of specific cells, but research is just in its
infancy."

Elsewhere on campus, the same recognition that the stem
cell field is too new to limit experimental designs is
replicated many times over. In Song's lab, both embryonic
and induced stem cells are used "because we don't know
which ones are going to be most effective in research,"
says Jason Chiang. "We're still not sure whether iPS cells
will behave the same as ESCs in a mouse." Until scientists
from all disciplines know and understand the differences,
they will need to experiment, comparatively and otherwise,
with all types of stem cells, he says.

Song adds that keeping all options open also could grow the
research field and guarantee there will be enough
scientists around to follow the most promising leads.
Somehow settling the bio-ethical concerns — Will
science devise a safe way to extract stem cells without
killing embryos? Will new methods to derive stem cells from
umbilical cord blood solve the problem? — could lead
to more federal research money, which will push the field
farther faster, he says.

"How do we train the next generation of researchers without
it? There have been so many people scared off. This field
is so broad that there are many avenues of research," Song
says. "We need as many people on it as possible."

The march
of science may now be ready to break into a
sprint, putting it in position to catch up with the wishes
of the public, which, polls show, overwhelmingly favors
increasing federal spending on stem cell research. Chi Dang
says that Johns Hopkins is ready to accommodate more stem
cell researchers. There's 40,000 square feet of lab space
set aside for the purpose, plus what he estimates to be
tens of millions of dollars in additional funding that
could finance a dozen or more investigators. Many of them
will work with embryonic stem cells. "What we're starting
to see now is a real variety of grant applications," says
Dang. "The projects we will work on now will try new things
— things we couldn't have imagined doing a year or so
ago."

The ascendancy of the Obama administration may indeed
answer the wishes of researchers, who say that ethical
questions should be broadened to consider the good that
embryos slated for eventual destruction could do for
humankind.

"If we accept as a society that in vitro fertilization is a
good thing, then the real question here is whether we
should throw away unused embryos, because we'll have plenty
of them," Dang says. "That's where we'll find a lot of
answers."